Secondary thalamic atrophy related to brain infarction may contribute to post-stroke cognitive impairment.

BACKGROUND AND PURPOSE: The thalamus is a key brain hub that is globally connected to many cortical regions. Previous work highlights thalamic contributions to multiple cognitive functions, but few studies have measured thalamic volume changes or cognitive correlates. This study investigates associations between thalamic volumes and post-stroke cognitive function. METHODS: Participants with non-thalamic brain infarcts (3-42 months) underwent MRI and cognitive testing. Focal infarcts and thalami were traced manually. In cases with bilateral infarcts, the side of the primary infarct volume defined the hemisphere involved. Brain parcellation and volumetrics were extracted using a standardized and previously validated neuroimaging pipeline. Age and gender-matched healthy controls provided normal comparative thalamic volumes. Thalamic atrophy was considered when the volume exceeded 2 standard deviations greater than the controls. RESULTS: Thalamic volumes ipsilateral to the infarct in stroke patients (n=55) were smaller than left (4.4 ± 1.4 vs. 5.4 ± 0.5 cc, p < 0.001) and right (4.4 ± 1.4 vs. 5.5 ± 0.6 cc, p < 0.001) thalamic volumes in the controls. After controlling for head-size and global brain atrophy, infarct volume independently correlated with ipsilateral thalamic volume (ß= -0.069, p=0.024). Left thalamic atrophy correlated significantly with poorer cognitive performance (ß = 4.177, p = 0.008), after controlling for demographics and infarct volumes. CONCLUSIONS: Our results suggest that the remote effect of infarction on ipsilateral thalamic volume is associated with global post-stroke cognitive impairment.

Determining Corticospinal Tract Injury from Stroke Using Computed Tomography.

INTRODUCTION: Damage to the corticospinal tract (CST) from stroke leads to motor deficits. The damage can be quantified as the amount of overlap between the stroke lesion and CST (CST Injury). Previous literature has shown that the degree of motor deficits post-stroke is related to the amount of CST Injury. These studies delineate the stroke lesion from structural T1-weighted magnetic resonance imaging (MRI) scans, often acquired for research. In Canada, computed tomography (CT) is the most common imaging modality used in routine acute stroke care. In this proof-of-principle study, we determine whether CST Injury, using lesions delineated from CT scans, significantly explains the variability in motor impairment in individuals with stroke. METHODS: Thirty-seven participants with stroke were included in this study. These individuals had a CT scan within the acute stage (7 days) of their stroke and underwent motor assessments. Brain images from CT scans were registered to MRI space. We performed a stepwise regression analysis to determine the contribution of CST injury and demographic variables in explaining motor impairment variability. RESULTS: Using clinically available CT scans, we found modest evidence that CST Injury explains variability in motor impairment (R2adj = 0.12, p = 0.02). None of the participant demographic variables entered the model. CONCLUSION: We show for the first time a relationship between CST Injury and motor impairment using CT scans. Further work is required to evaluate the utility of data derived from clinical CT scans as a biomarker of stroke motor recovery.

Progression of limb apraxia in corticobasal syndrome: neuropychological and functional neuroimaging report of a case series.

The current study described the progression of limb apraxia in seven corticobasal syndrome patients through a comprehensive battery, including both gesture production tasks and conceptual tool/action knowledge tasks. The examination of the behavioral and neuroimaging (SPECT) data revealed two patient subgroups. One group consisted of patients with preserved conceptual tool/action knowledge, relatively mild gesture production and neuropsychological deficits with few significantly hypoperfused regions of interest. The other group consisted of those whose conceptual tool/action knowledge and general cognition eventually deteriorated and who were quite severely affected in their gesture production performance. These patients were characterized by bilateral hypoperfusion in parietal regions and in one case bilateral anterior cingulate regions.

Object alternation: a novel probe of medial frontal function in frontotemporal dementia.

We studied behavioral variant frontotemporal dementia (bvFTD) using object alternation (OA) as a novel probe of cognition. This task was adopted from animal models and is sensitive to ventrolateral-orbitofrontal and medial frontal function in humans. OA was administered to bvFTD patients, normal controls, and a dementia control group with Alzheimer disease (AD). Two other frontal lobe measures adopted from animal models were administered: delayed response (DR) and delayed alternation (DA). Brain volumes were measured using the semiautomatic brain region extraction method. Compared with the normal controls, bvFTD patients were significantly impaired on OA and DR. For OA and DR, sensitivities and specificities were 100% and 51.5% (cutoff=22.5 errors) and 9.5% and 98% (cutoff=1.5 errors), respectively. Negative predictive value (NPV) for OA was 100% at all prevalence rates. Comparing AD with bvFTD, there were no significant differences on OA, DR, or DA. Nevertheless, positive predictive value (PPV) and NPV were good at all prevalence rates for OA (cutoff=36.5 errors) and DA (cutoff=6 errors); PPV was good for DR (cutoff=9 errors). Error scores above cutoffs favored diagnosis of AD. Performance on OA was significantly related to medial frontal gray matter atrophy. OA, together with DR and DA, may facilitate assessment of bvFTD as a novel probe of medial frontal function.

Increased brain volumetric measurement precision from multi-site 3D T1-weighted 3 T magnetic resonance imaging by correcting geometric distortions.

PURPOSE: Magnetic resonance imaging (MRI) scanner-specific geometric distortions may contribute to scanner induced variability and decrease volumetric measurement precision for multi-site studies. The purpose of this study was to determine whether geometric distortion correction increases the precision of brain volumetric measurements in a multi-site multi-scanner study. METHODS: Geometric distortion variation was quantified over a one-year period at 10 sites using the distortion fields estimated from monthly 3D T1-weighted MRI geometrical phantom scans. The variability of volume and distance measurements were quantified using synthetic volumes and a standard quantitative MRI (qMRI) phantom. The effects of geometric distortion corrections on MRI derived volumetric measurements of the human brain were assessed in two subjects scanned on each of the 10 MRI scanners and in 150 subjects with cerebrovascaular disease (CVD) acquired across imaging sites. RESULTS: Geometric distortions were found to vary substantially between different MRI scanners but were relatively stable on each scanner over a one-year interval. Geometric distortions varied spatially, increasing in severity with distance from the magnet isocenter. In measurements made with the qMRI phantom, the geometric distortion correction decreased the standard deviation of volumetric assessments by 35% and distance measurements by 42%. The average coefficient of variance decreased by 16% in gray matter and white matter volume estimates in the two subjects scanned on the 10 MRI scanners. CONCLUSION: Geometric distortion correction using an up-to-date correction field is recommended to increase precision in volumetric measurements made from MRI images.

Imaging genetics in multiple sclerosis: a volumetric and diffusion tensor MRI study of APOE ε4.

Evidence linking the ε4 allele of APOE to more severe brain MRI abnormalities in multiple sclerosis (MS) has been conflicting and limited to studies of lesion load and whole brain atrophy. The purpose of the present study was to determine whether the ε4 allele of APOE is associated with more extensive brain pathology in MS using structural and diffusion tensor MRI. Using a case-control design, 43 MS patients with the ε4 allele and 47 ε4 negative MS patients underwent structural and diffusion tensor imaging (DTI) at 3T. Hypo- and hyperintense lesion volumes, whole brain and medial temporal volumes, and DTI parameters (fractional anisotropy (FA) and mean diffusivity (MD)) in normal-appearing brain tissue and lesions were compared between the groups. ε4+ and ε4- MS patients were well-matched on demographic characteristics, disease variables, and proportions receiving disease-modifying therapy. ε4+ and ε4- patients did not differ on any MRI or DTI measure. This study refutes a role for the ε4 allele in MRI abnormalities in MS, particularly those linking ε4 to greater T1 hypointense lesion volume and brain atrophy. Previous work on this putative gene-MRI relationship is extended by comparing DTI measures within lesions and normal-appearing brain tissue. A lack of differences in medial temporal regions, areas that have been linked to ε4-associated changes in health and disease, further supports the conclusion that that ε4 is not associated with more subtle MRI markers of brain pathology in MS.

Correlating lesion size and location to deficits after ischemic stroke: the influence of accounting for altered peri-necrotic tissue and incidental silent infarcts.

BACKGROUND: Investigators frequently quantify and evaluate the location and size of stroke lesions to help uncover cerebral anatomical correlates of deficits observed after first-ever stroke. However, it is common to discover silent infarcts such as lacunes in patients identified clinically as 'first-ever' stroke, and it is unclear if including these incidental findings may impact lesion-based investigations of brain-behaviour relationships. There is also debate concerning how to best define the boundaries of necrotic stroke lesions that blend in an ill-defined way into surrounding tissue, as it is unclear whether including this altered peri-necrotic tissue region may influence studies of brain-behaviour relationships. Therefore, for patients with clinically overt stroke, we examined whether including altered peri-necrotic tissue and incidental silent strokes influenced either lesion volume correlations with a measure of sensorimotor impairment or the anatomical localization of this impairment established using subtraction lesion analysis. METHODS: Chronic stroke lesions of 41 patients were manually traced from digital T1-MRI to sequentially include the: necrotic lesion core, altered peri-necrotic tissue, silent lesions in the same hemisphere as the index lesion, and silent lesions in the opposite hemisphere. Lesion volumes for each region were examined for correlation with motor impairment scores, and subtraction analysis was used to highlight anatomical lesion loci associated with this deficit. RESULTS: For subtraction lesion analysis, including peri-necrotic tissue resulted in a larger region of more frequent damage being seen in the basal ganglia. For correlational analysis, only the volume of the lesion core was significantly associated with motor impairment scores (r = -0.35, p = 0.025). In a sub-analysis of patients with small subcortical index lesions, adding silent lesions in the opposite hemisphere to the volume of the index stroke strengthened the volume-impairment association. CONCLUSIONS: Including peri-necrotic tissue strengthened lesion localization analysis, but the influence of peri-necrotic tissue and incidental lesions on lesion volume correlations with motor impairment was negligible barring a small index lesion. Overall, the potential influence of incidental lesions and peri-necrotic tissue on brain-behaviour relationships may depend on the characteristics of the index stroke and on whether one is examining the relationship between lesion volume and impairment or lesion location and impairment.

Ontario Neurodegenerative Disease Research Initiative (ONDRI): Structural MRI Methods and Outcome Measures.

The Ontario Neurodegenerative Research Initiative (ONDRI) is a 3 years multi-site prospective cohort study that has acquired comprehensive multiple assessment platform data, including 3T structural MRI, from neurodegenerative patients with Alzheimer's disease, mild cognitive impairment, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and cerebrovascular disease. This heterogeneous cross-section of patients with complex neurodegenerative and neurovascular pathologies pose significant challenges for standard neuroimaging tools. To effectively quantify regional measures of normal and pathological brain tissue volumes, the ONDRI neuroimaging platform implemented a semi-automated MRI processing pipeline that was able to address many of the challenges resulting from this heterogeneity. The purpose of this paper is to serve as a reference and conceptual overview of the comprehensive neuroimaging pipeline used to generate regional brain tissue volumes and neurovascular marker data that will be made publicly available online.

Periodic Limb Movements and White Matter Hyperintensities in First-Ever Minor Stroke or High-Risk Transient Ischemic Attack.

Study Objectives: Emerging evidence suggests that periodic limb movements (PLMs) may contribute to the development of cerebrovascular disease. White matter hyperintensities (WMHs), a widely accepted biomarker for cerebral small vessel disease, are associated with incident stroke and death. We evaluated the association between increased PLM indices and WMH burden in patients presenting with stroke or transient ischemic attack (TIA), while controlling for vascular risk factors and stroke severity. Methods: Thirty patients presenting within 2 weeks of a first-ever minor stroke or high-risk TIA were prospectively recruited. PLM severity was measured with polysomnography. WMH burden was quantified using the Age Related White Matter Changes (ARWMC) scale based on neuroimaging. Partial Spearman's rank-order correlations and multiple linear regression models tested the association between WMH burden and PLM severity. Results: Greater WMH burden was correlated with elevated PLM index and stroke volume. Partial Spearman's rank-order correlations demonstrated that the relationship between WMH burden and PLM index persisted despite controlling for vascular risk factors. Multivariate linear regression models revealed that PLM index was a significant predictor of an elevated ARWMC score while controlling for age, stroke volume, stroke severity, hypertension, and apnea-hypopnea index. Conclusion: The quantity of PLMs was associated with WMH burden in patients with first-ever minor stroke or TIA. PLMs may be a risk factor for or marker of WMH burden, even after considering vascular risk factors and stroke severity. These results invite further investigation of PLMs as a potentially useful target to reduce WMH and stroke burden.

Peripheral inflammatory markers indicate microstructural damage within periventricular white matter hyperintensities in Alzheimer's disease: A preliminary report.

INTRODUCTION: White matter hyperintensities (WMH) presumed to reflect cerebral small vessel disease and increased peripheral inflammatory markers are found commonly in Alzheimer's disease (AD), but their interrelationships remain unclear. METHODS: Inflammatory markers were assayed in 54 elderly participants (n = 16 with AD). Periventricular WMH were delineated from T1, T2/proton density, and fluid-attenuated magnetic resonance imaging using semiautomated fuzzy lesion extraction and coregistered with maps of fractional anisotropy (FA), a measure of microstructural integrity assessed using diffusion tensor imaging. RESULTS: Mean FA within periventricular WMH was associated with an inflammatory factor consisting of interleukin (IL)-1ß, tumor necrosis factor, IL-10, IL-21, and IL-23 in patients with AD (ρ = -0.703, P = .002) but not in healthy elderly (ρ = 0.217, P = .190). Inflammation was associated with greater FA in deep WMH in healthy elderly (ρ = 0.425, P = .008) but not in patients with AD (ρ = 0.174, P = .520). DISCUSSION: Peripheral inflammatory markers may be differentially related to microstructural characteristics within the white matter affected by cerebral small vessel disease in elders with and without AD.

Lesion Characteristics of Individuals With Upper Limb Spasticity After Stroke.

This study explores the relationship between lesion location and volume and upper limb spasticity after stroke. Ninety-seven stroke patients (51 with spasticity) were included in the analysis (age = 67.5 ± 13.3 years, 57 males). Lesions were traced from computed tomography and magnetic resonance images and coregistered to a symmetrical brain template. Lesion overlays from the nonspastic group were subtracted from the spastic group to determine the regions of the brain more commonly lesioned in spastic patients. Similar analysis was performed across groups of participants whose upper limb (elbow or wrist) Modified Ashworth Scale (MAS) score ranged from 1 (mild) to 4 (severe). Following subtraction analysis and Fisher's exact test, the putamen was identified as the area most frequently lesioned in individuals with spasticity. More severe spasticity was associated with a higher lesion volume. This study establishes the neuroanatomical correlates of poststroke spasticity and describes the relationship between lesion characteristics and the severity of spasticity using mixed brain imaging modalities, including computed tomography imaging, which is more readily available to clinicians. Understanding the association between lesion location and volume with the development and severity of spasticity is an important first step toward predicting the development of spasticity after stroke. Such information could inform the implementation of intervention strategies during the recovery process to minimize the extent of impairment.

Lesion Explorer: a video-guided, standardized protocol for accurate and reliable MRI-derived volumetrics in Alzheimer's disease and normal elderly.

Obtaining in vivo human brain tissue volumetrics from MRI is often complicated by various technical and biological issues. These challenges are exacerbated when significant brain atrophy and age-related white matter changes (e.g. Leukoaraiosis) are present. Lesion Explorer (LE) is an accurate and reliable neuroimaging pipeline specifically developed to address such issues commonly observed on MRI of Alzheimer's disease and normal elderly. The pipeline is a complex set of semi-automatic procedures which has been previously validated in a series of internal and external reliability tests(1,2). However, LE's accuracy and reliability is highly dependent on properly trained manual operators to execute commands, identify distinct anatomical landmarks, and manually edit/verify various computer-generated segmentation outputs. LE can be divided into 3 main components, each requiring a set of commands and manual operations: 1) Brain-Sizer, 2) SABRE, and 3) Lesion-Seg. Brain-Sizer's manual operations involve editing of the automatic skull-stripped total intracranial vault (TIV) extraction mask, designation of ventricular cerebrospinal fluid (vCSF), and removal of subtentorial structures. The SABRE component requires checking of image alignment along the anterior and posterior commissure (ACPC) plane, and identification of several anatomical landmarks required for regional parcellation. Finally, the Lesion-Seg component involves manual checking of the automatic lesion segmentation of subcortical hyperintensities (SH) for false positive errors. While on-site training of the LE pipeline is preferable, readily available visual teaching tools with interactive training images are a viable alternative. Developed to ensure a high degree of accuracy and reliability, the following is a step-by-step, video-guided, standardized protocol for LE's manual procedures.

Region-Based Partial Volume Correction Techniques for PET Imaging: Sinogram Implementation and Robustness.

Background/Purpose. Limited spatial resolution of positron emission tomography (PET) requires partial volume correction (PVC). Region-based PVC methods are based on geometric transfer matrix implemented either in image-space (GTM) or sinogram-space (GTMo), both with similar performance. Although GTMo is slower, it more closely simulates the 3D PET image acquisition, accounts for local variations of point spread function, and can be implemented for iterative reconstructions. A recent image-based symmetric GTM (sGTM) has shown improvement in noise characteristics and robustness to misregistration over GTM. This study implements the sGTM method in sinogram space (sGTMo), validates it, and evaluates its performance. Methods. Two 3D sphere and brain digital phantoms and a physical sphere phantom were used. All four region-based PVC methods (GTM, GTMo, sGTM, and sGTMo) were implemented and their performance was evaluated. Results. All four PVC methods had similar accuracies. Both noise propagation and robustness of the sGTMo method were similar to those of sGTM method while they were better than those of GTMo method especially for smaller objects. Conclusion. The sGTMo was implemented and validated. The performance of the sGTMo in terms of noise characteristics and robustness to misregistration is similar to that of the sGTM method and improved compared to the GTMo method.

Microbleed topography, leukoaraiosis, and cognition in probable Alzheimer disease from the Sunnybrook dementia study.

BACKGROUND: Microbleeds are hemosiderin deposits around small vessels and are well visualized with T2*-weighted gradient-recalled echo (GRE) imaging. OBJECTIVES: To determine frequency and topography of microbleeds in Alzheimer disease (AD) and to assess their association with leukoaraiosis and cognition. DESIGN: Case-control cross-sectional analysis. Microbleeds were counted using GRE imaging. Leukoaraiosis was rated on T2-weighted and proton density-weighted scans using the Age-Related White Matter Changes Rating Scale (ARWMC). Neuropsychological tests indexed cognition. SETTING: The Cognitive Neurology Clinic, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. PATIENTS: Individuals with probable AD (n = 80) and healthy controls (n = 25) from a longitudinal cohort with GRE sequences as part of standard imaging protocol (2002-2006). RESULTS: Microbleeds occurred in 29% of patients with AD and 12% of controls and were multiple (> 1) in 48% of patients with AD and 33% of controls. There was lobar (vs centrencephalic) predominance in 92% of AD patients, with occipital lobes accounting for 57% of these microbleeds. The ARWMC scores (P < .005) were significantly higher in AD patients with microbleeds than in those without, and microbleeds correlated with total (r = 0.39, P = .01) and parietooccipital (r = 0.28, P < .01) ARWMC scores. We were unable to demonstrate an association between microbleeds (or leukoaraiosis) and cognitive performance. CONCLUSIONS: Occipital predominance of microbleeds with corresponding parietooccipital leukoaraiosis has not been well described in prior imaging studies of AD. Microbleeds were frequent, often multiple, and predicted greater leukoaraiosis. These findings illustrate the complexity of AD vasculopathy and the need for additional studies in dementia and stroke populations.